The objective of this project is to investigate how variation within obesity genes may influence the onset and severity of multiple sclerosis (MS). MS is an immune-mediated, demyelinating disorder believed to be caused by both genetic and environmental factors. Recently, individuals with childhood or adolescent obesity have demonstrated greater than a twofold increased risk of MS compared to those at a normal weight in numerous studies, though the biological mechanism through which this occurs is unknown. It is plausible that there are common genetic and biologic pathways that contribute to obesity and result in susceptibility of MS, as both MS and obesity are characterized as inflammatory diseases. Forty genes dispersed throughout the genome have been found to be associated with obesity-related traits; however, how they may relate to MS onset or disease severity has not been previously investigated. The overall hypothesis of this project is that genetic variants associated with obesity will demonstrate both direct and indirect effects on MS onset or severity. This project will utilize high-quality genotype data, detailed body mass index histories, and other clinical characteristics from ~1,500 cases and ~12,000 controls to address three related hypotheses. First, genetic variants associated with obesity will demonstrate both direct and indirect effects via body mass index on MS onset or severity. A regression-based mediation analysis, adjusting for known confounders and genetic ancestry, will be utilized to test for the presence of these effects. Second, pathway analysis of obesity and established MS genes will identify biological pathways that may influence risk of MS onset or severity. Pathway analyses of established obesity and MS associated genes will be conducted using the Disease Association Protein-Protein Link Evaluator (DAPPLE). Third, observed effects of obesity variants on MS onset or severity will be replicated in an independent dataset of MS cases and controls. Analyses will be pursued in a second dataset of MS cases and controls to confirm significant findings. The importance in MS susceptibility and severity of both genetic and environmental factors, including obesity, will be demonstrated through this research and provide new insight into the etiology of this debilitating condition and others where a role for obesity is suspected.